An Interview with Kirsten Mundt of ESBATech.

A fundamental paradigm shift from traditional to genomics-based drug discovery is taking place. This is due not only to the vast field of opportunity opened up by the advent of the new technologies, but also because of the diminishing returns, in terms of new drugs reaching the market, of traditional drug discovery. With steadily growing drug development costs, depleted pipelines, and no prospective blockbusters on the horizon, many companies will be relying on novel targets to reach or maintain profitability. In this article Kirsten Mundt, Business Development Manager at ESBATech, explains why the issue of target validation will emerge as one of the most critical problems in drug discovery today. This commentary is excerpted from a new Cambridge Healthtech Institute report, Post-Genomic Target Validation: Next Generation Approaches and Tools for Optimizing Target Selection.

Today, target validation is probably just as critical as it was perceived to be a few years ago.
However, overall, I believe the focus on target validation has diminished to some extent. Due to the current economical state within the industry, and judging by the extent of interest in ESBATech’s technology which addresses target validation, big pharma are currently much more interested in working on later-stage projects. But in order to keep pipelines full, new targets necessarily need to be fed in. For these novel targets to be of good quality, they must be thoroughly validated before embarkation on a discovery and development program. So while there seems to be less interest at the moment, target validation is just as important as it always has been.

Resurgence in target validation work will occur over time. Once companies have moved compounds into development and realize that the top-end of their pipeline is empty, then they will start looking for new targets and ways to validate them. There are still a lot of uncharacterized proteins and genes out there, and researchers will want to find out what their functions are and whether they are disease targets that lend themselves to a drug discovery program.

One approach to target validation is inactivation of protein function to see what happens. This practice mimics the possible effect of a drug, particularly an inhibitory drug. ESBATech has set up a platform that allows the selection of antibodies that are highly soluble and very stable inside cells—the latter is an unusual property for most antibodies. Using our platform, we can select intracellularly stable antibodies that neutralize protein function. The great advantage of this approach over other target validation approaches is that it does not eliminate the whole protein. For example, gene knockout studies and RNAi both knock out the total gene and the total protein—these techniques do not act on the expressed protein. These technologies therefore cannot be used to address certain protein domains. The use of neutralizing antibodies allows you to target specific domains and, in that way, obtain information with respect to which domain might be druggable. Obviously, if you eliminate the entire protein, you will not be able to obtain any specific, domain-related information.

ESBATech has developed a proprietary method to select intracellularly stable neutralizing antibodies that can be employed for such a domain-knock-out approach. Initially, ESBATech has selected a panel of super-stable frameworks in an antigen-independent screen. On the basis of these proprietary frameworks, libraries have been built that cover the maximum diversity of sequence and spatial space. These libraries are used to select specific antibodies in a yeast cell-based, high-throughput screening system. In the area of target validation, we have had two successful, proof-of-principle studies. In the first one, we showed that intracellularly stable, single-chain antibodies targeted against the dimerization domain of the yeast transcriptional activator Gcn4 significantly reduced its activation function. In another study, we targeted an intracellular kinase (Polo-Like-Kinase 1[Plk1], involved in cell division/mitotic regulation), against which we raised a whole panel of antibodies, such that they decorated the entire protein. We were able to show that some of these antibodies were actually neutralizing, whereas others did not have this effect. Again, this provided critical information with respect to which domain of the protein might be more important to target for purposes of drug discovery.

With the second pillar of our antibody program, ESBATech is exploiting the properties of these antibodies (the facts that they are highly stable and well expressed) for specific therapeutic applications, where they possess a unique advantage over conventional antibodies. ESBATech’s antibodies are not full-length antibodies, although they could be grafted into full IgG molecules. We use antibody fragments, such as single-chain fragments and Fab fragments, and we have recently (May 2003) reached a licensing agreement with Micromet/Enzon covering the single-chain antibody format and derivatives thereof. Fab and the scFv antibody lack the Fc part of the full-length antibody (also called the effector domain). Therefore, a number of immune responses, such as activation of the complement cascade, are not induced. Depending on the application, this can be a distinct advantage. (For other uses, the function of the effector domain may also be desired, so it depends on the application.)

In addition to its internal programs, ESBATech has established research alliances with academic institutions, as well as one in the field of Alzheimer’s disease with Hoffmann-La Roche Ltd. The research alliance with Hoffmann-La Roche has been successfully completed. The academic collaborations are in various fields with the University of Zurich. (One is with Prof. Amedeo Caflisch on in silico evaluation of small compound inhibitors for BACE, a different drug discovery program at ESBATech, and another one is with Prof. Andreas Plückthun at the University of Zurich on further characterization of the stable antibody frameworks). ESBATech’s technology provides a powerful way to select antibodies. So in addition to ESBATech’s internal, product-focused program, we are also using the technology to select extremely stable, soluble, and highly expressed therapeutic antibodies.

ESBATech seeks to build upon its proprietary technologies to become a fully integrated drug discovery company. Currently, our work is in the research and preclinical stages. At this point, we would seek to partner compounds at some phase in late discovery (i.e., ADME/Tox studies) prior to clinical trials. I think that as ESBATech grows and gains more experience, as a lot of small biotech companies do, we will be able to move compounds further through the development process independently.

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